Sporadic Alzheimer?s disease (AD) likely involves multiple genetic and environmental risk factors that lead to amyloid ? (A?) dyshomeostasis. We have recently identified the ?2A adrenergic receptor (?2AAR) as a novel factor that promotes amyloidogenic processing of the amyloid precursor protein (APP) and A? generation through G protein signaling in neurons. Activation of ?2AAR disrupts APP interaction with SorLA, a neuronal sorting receptor that has recently emerged as a risk factor for sporadic AD. Genetic deficiency and pharmacological blockade of ?2AAR lead to reduced A? generation and improved AD-related neuropathology. Furthermore, our unpublished data using both cultured cells and animal models suggest that A?42 allosterically modulates ?2AAR to enhance ?2AAR activity. Collectively, our data suggest a novel positive feedback relationship between ?2AAR activation and A? generation, which would exacerbate AD-related pathophysiology. Significantly, we have collected initial human evidence supporting the involvement of ?2AAR in AD. First, our initial analysis of postmortem brains reveals a trend of increased ?2AAR activity in AD cases. Secondly, our biostatistical analysis of the National Alzheimer?s Coordinating Center (NACC) database suggests that chronic activation of ?2AR exacerbates disease progression in AD patients. Collectively, our data strongly support that ?2AAR represents a previously unappreciated pathogenic factor and therapeutic target for AD. The primary objective of this proposal is to test the central hypothesis that ?2AAR activation and A? generation form a positive feedback loop to exacerbate AD-associated pathophysiology, and that blocking this feedback loop slows AD progression. We will 1) address the mechanism of how ?2AAR signaling regulates SorLA-dependent APP processing; 2) uncover the association between ?2AAR activity and A? progression in AD; 3) determine the efficacy of ?2AAR blockers in reducing pathological and cognitive deficits in preclinical AD models in which A? pathology is developed. Noradrenergic degeneration is a frequently observed phenomenon in AD. However, the potential role of the noradrenergic dysfunction in driving pathogenesis in sporadic AD has not been adequately addressed. We will integrate the use of human biosamples with cell-based and animal models to reveal the mechanistic contribution of an essential noradrenergic component, ?2AAR, to AD pathogenesis. Our studies could lead to development of new therapeutic strategies for AD treatment.